5-(pyridylalkyl)-pyridoindole derivatives



United States Patent Ofi-ce 3,522,262 -(PYRIDYLALKYL)-PYRIDOINDOLE DERIVATIVES Leo Berger, Montclair, and Alfred John Corraz, Wayne, N.J., assignors to Holfmann-La Roche Inc., Nutley,

N.J., a corporation of New Jersey No Drawing. Filed Sept. 10, 1968, Ser. No. 758,712 The portion of the term of the patent subsequent to Nov. 5, 1985, has been disclaimed Int. Cl. (307d 31/42 US. Cl. 260-296 23 Claims ABSTRACT OF THE DISCLOSURE S-(pyridylalkyl)pyridoindole derivatives having antiallergic activity, prepared by the condensation of the correspondingly substituted 4-piperidones and N-amino-N- arylaminoalkylpyridines, are described.

BRIEF SUMMARY OF THE INVENTION The invention relates to 5-(pyridylalkyl)pyridoindole derivatives, processes and intermediates for the preparation thereof. More particularly, the invention relates to compounds of the formula r B5 CHRQ I I I wherein R is hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

The compounds of Formula I are useful as antihistaminic and antiallergic agents.

DETAILED DESCRIPTION OF THE INVENTION The end products of the invention are characterized by formula wherein R is hydrogen, lower alkyl, benzoyl or benzyl; R R R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxy, lower alkoXycarbonyl, carboxy, hydroxyrnethyl or trifluoromethyl, pro- 3,522,262 Patented July 28, 1970 vided that at least one of R R R and R is other than hydrogen; R is hydrogen or lower alkyl; and A is wherein R is hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term lower alkyl is to be understood to means a straight or branched chain alkyl group of 1 to '6 carbon atoms, such as methyl, ethyl, isopropyl, butyl, pentyl, hexyl, and the like; methyl is preferred. The term halogen is to be understood to mean all of the halogens, i.e., bromine, chlorine, fluorine and iodine; bromine and chlorine are preferred. The term lower alkoxy is to be understood to mean a lower alkyl ether group in which the lower alkyl moiety is as described above, such as methoxy, ethoxy, propoxy, butoxy and the like; methoXy is preferred.

Illustrative of the compounds of Formula I are the following:

8-chloro- 1, 3 ,4,5-tetrahydro-2-methyl-5- (a-methyl-3- pyridylmethyl) -2H-pyrido [4,3-b] indole;

8 -chloro-1, 3,4, 5-tetrahydro-2-methyl-5 u-methyl-Z- pyridylmethyl -2H-pyrido [4,3 -b] indole;

8-chloro-1,3,4,5-tetrahydro-2-n1ethyl-5- u-methyl-( 6- methyl-Z-pyridyl) methyl] -2H-pyrido [4,3-b] indole;

8-chloro-1,3,4,S-tetrahydro-Z-methyl-S- a-methyl- 6- methyl-3-pyridyl) methyl] 2H-pyrido [4,3 -b] indole;

8-bromo-1,3,4,5-tetrahydro-2-methyl-5-(a-methyl-3- pyridylmethyl) -2H-pyrido [4,3-b] indole;

8-chloro- 1,3 ,4, S-tetrahydro -2-methyl-5 a-methyl-4- pyridylmethyl) -2H-pyrido [4,3-b1indole;

l, 3 ,4,5-tetrahydro-2, 8-dimethyl-5 (a-methyl-3 -pyridylmethyl) -2-H-pyrido [4,3-b indole;

l, 3 ,4,5 -tetrahydro-8-methoxy-2-methyl-S- a-methyl-3- pyridylmethyl) -2H-pyrido [4,3 -b] indole;

1,3,4,5-tetrahydro-2,7,S-trimethyl-S- (a-methyl-3- pyridylmethyl) -2H-pyrido [4,3 -b] indole;

1,3,4, S-tetrahydro-Z, 8,9-trimethyl-5- a-methyl-3- pyridylmethyl) -2H-pyrido [4,3 -b] indole;

8-chloro-1,3 ,4,5-tetrahydro-2-methyl-5- 3-pyridylmethyl)-ZH-pyrido [4,3-b1indole;

8-chloro-1,3 ,4, S-tetrahydro-Z-methyl-S- (4-pyridylmethyyl) -2H-pyrido [4,3-b indole; and

8-chloro-1, 3 ,4,5-tetrahydro-2-methyl-5- (2-pyridylmethyl) -2H-pyrido [4, 3 -b] indole.

The novel end products of the invention, i.e., the compounds of Formula I, wherein one or more of R R R or R is other than carboxy or hydroxymethyl, can be prepared according to the procedure set forth in Reaction Scheme 1:

II III wherein R R R R R R and A are as previously described.

In Reaction Scheme I, a substituted aniline of Formula II, which are known compounds or are analogs of known compounds readily obtained by known procedures, is condensed with a pyridine aldehyde or pyridylalkyl ketone of Formula III, which are also known compounds or are analogs of known compounds readily obtained by known procedures, to yield the Schitf base of Formula IV. The condensation is carried out at reflux temperatures, preferably in the presence of an inert organic solvent such as, for example, benzene, toluene and the like. The condensation is suitably carried out at an elevated temperature, preferably at a temperature between about room temperature and the boiling point of the reaction mixture; the preferred temperature range is the reflux temperature of the reaction mixture. Conveniently, an acid catalyst such as paratoluenesulfonic acid and the like may be used to accelerate the reaction.

The Schiif base of Formula IV is converted to the arylaminoalkylpyridine of Formula V utilizing a reducing agent such as, for example, sodium borohydride, or a hydrogenation catalyst, e.g., palladium-on-carbon and the like. Conveniently, an inert organic solvent such as, for example, alkanols and the like, may be utilized. The reduction is suitably carried out at a temperature in the range of about to 100 C.

The arylaminoalkylpyridine of Formula V is converted to the N-nitrosoamine of Formula VI utilizing a nitrosating agent such as, for example, nitrous acid, which can be conveniently prepared in situ from hydrochloric acid and sodium nitrite. The reaction is suitably carried out in the presence of an inert organic solvent, for example, a lower alkanol such as methanol, ethanol, propanol and the like, preferably at a low temperature, i.e., at a temperature between about 0 and about 25 C.

The N-nitrosoamine of Formula VI is converted to the N-amino-N-arylaminoalkylpyridine of Formula VII utilizing a reducing agent, preferably a mild reducing agent such as, for example, zinc. The reduction is suitably carried out in the presence of an aqueous acid at a temperature below room temperature, preferably between about 0 and 20 C.

The condensation of the N-amino-N-arylaminoalkylpyridine of Formula VII with the piperidone of Formula VIII, which are known compounds or are analogs of known compounds readily obtained by known procedures, to yield the S-(pyridylalkyl)-pyridoindole of Formula I is suitably carried out in the presence of an inert organic solvent such as, for example, alkanols, benzene, toluene and the like. The condensation is suitably carried out at an elevated temperature, preferably at a temperature between about room temperature and the boiling point of the reaction mixture; most preferred are temperatures in the range between about 20 and C.

The compounds of Formula I, wherein one or more of R R R and R is hydroxymethyl, can be prepared by treating the respective compound of Formula I, wherein correspondingly one or more of R R R and R is methoxycarbonyl, with a reducing agent such as, for example, lithium aluminum hydride and the like.

The compounds of Formula I, wherein one or more of R R R and R is carboxy, can be prepared by treating the respective compound of Formula I, wherein correspondingly one or more of R R R and R is methoxycarbonyl, with a hydrolyzing agent such as, for example, sodium hydroxide and the like.

Preferred end-products of the invention are characterized by the formula ]/\I\I 'RI Q HCR.

wherein R is hydrogen, lower alkyl, benzoyl or benzyl; R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxycarbonyl, carboxy, lower alkoxy, hydroxymethyl or trifluoromethyl, provided that at least one of R or R is other than hydrogen; R is hydrogen or lower alkyl; and A is wherein R is hydrogen or lower alkyl and their pharmaceutically acceptable acid addition salts. Of these, the more preferred are those wherein R is methyl, R and R are chloro, bromo or methyl and R is methyl and the most preferred are those wherein. R is methyl, R is chloro, bromo or methyl, R is hydrogen and R is methyl.

The compounds of Formula I form acid addition salts and such salts are also within the scope of the invention. The compounds of Formula I form pharmaceutically acceptable acid addition salts with both pharmaceuticlly acceptable organic and inorganic acids. Suitable organic acids are, for example, maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid, succinic acid, citric acid and the like. Suitable inorganic acids are, for example, the hydrohalic acids, e.g. hydrochloric acid and hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and the like. The acid addition salts are readily obtainable by the usual techniques for the preparation of salts from acids.

The compounds of Formula I of the present invention can be formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, etc. Furthermore, the compounds of this invention can be embodied into and administered in the form of suitable hard or soft capsules. The identity of the inert adjuvant materials which are used in formulating the present compounds into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materials, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, etc., can be incorporated, if desired, into such formulations.

The compounds of Formula I and their pharmaceutically acceptable acid addition salts are distinguishable by their antiallergic activity, more particularly their antihistaminic activity, and therefore are useful antihistaminic agents. Particularly pronounced is the antiallergic activity of 8 chloro l,3,4,5-tetrahydro-2-methyl-5-(a-methyl-3- pyridylmethyl)-2H-pyrido-[4,3-b]indole and 8-chloro- 1,3,4,5 tetrahydro 2 methyl-5-(Z-pyridylmethyl)-2H- pyrido[4,3-b]indole.

The useful antihistaminic activity of the compounds of Formula I is demonstrated in warm-blooded animals utilizing the standard procedures. For example, five to ten guinea pigs per dose level are orally administered the test compound one hour before intracardial injection of histamine. A 0.55 percent solution of histamine di phosphate is administered at a level of 1 mg./kg. (LD dose. The percent protection from death is used to determine the ED value for the test compound. ED s are calculated by the Miller and Tainter method (Proc. Soc. Exptl. Biol. Med. 57: 261, 1944).

When 8-chloro-l,3,S-tetrahydro-Z-methyl-S-(Z-pyridylmethyl)-2H-pyrido[4,3-blindole, which has demonstrated an LD of 354 mg./kg. p.o., is utilized as the test substance, an ED of 0.17 is obtained.

When 8 chloro 1,3,4,5 tetrahydro-2-methyl-5-(arnethyl-3-pyridylmethyl)-2H-pyrido[4,3-b1indole is utilized as the test substance, an ED of 0.19 is obtained.

The compounds of the Formula I and their pharmaceutically acceptable acid addition salts have effect qualitatively similar to those of chlorpheniramine, known for its therapeutic use and properties. Thus, the compounds of the Formula I demonstrate a pattern of activity associated with anti-allergies of known efficacy and safety.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the therapeutic effect desired in the species of animal shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.

The following nonlimiting examples further illustrate the invention. All parts are by weight and all temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 3-[a-methyl-(4-chloroanilino) methyl] pyridine 01 CO CH3 01 y N NE H2 \N I A mixture of 102 g. of p-chloroaniline, 100 g. of 3- acetylpyridine, 100 mg. of p-toluenesulfonic acid and 600 ml. of benzene was stirred at reflux temperature for 48 hours. The theoretical quantity of water from the reaction was removed by means of a Dean-Stark trap and the reaction mixture was concentrated to a syrup under reduced pressure. The resultant Schiifs base was dissolved in 400 ml. of ethanol. To this solution was added a suspension of 60 g. of sodium borohydride in 400 m1. of ethanol over the course of 2 hours. The reaction mixture was then refluxed for 2 /2 hours and allowed to stand at room temperature overnight.

The solution was then steam distilled to remove any unreacted starting materials and the residue was thoroughly extracted with ether (4x250 ml.). The ether solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The solid residue was crys- 3-[a-methyl-(p-toluidino)methyl]pyridine, melting at 1113", its dihydrochloride salt melting at 187 [from p-toluidine and 3-acetylpyridine];

3-[a-methyl-(p-bromoanilino)methyl] pyridine, melting at 131", its dihydrochloride salt melting at 193-l94 [from p-bromoaniline and 3-acetylpyridine];

3- [a-methyl- (p-methoxyanilino methyl] pyridine, melting at 7071.5 [from p-anisidine and 3-acetylpyridine]; 3- a-methyl- 3,4-dimethylanilino) methyl] pyridine, melting at 91.592.5 [from 3,4-dimethylaniline and 3-acetylpyridine] 2-[a-methyl-(4-chloroanilino)methyl]pyridine, melting at 93-945", its dihydrochloride salt melting at 139-142 [from Z-acetylpyridine and p-chloroaniline];

2 [rx-methyl-(4-chloroanilino) methyl] 6 methylpyridine, melting at 9596, its dihydrochloride salt melting at 219220 [from 2-acetyl-G-methylpyridine and p-chloroaniline] 5-[at-methyl(4-chloroanilino) methyl] 2 methylpyridine, melting at ll4115 [from Z-methyl-S-acetylpyridine and p-chloroaniline];

3-[or-methyl(4-chloroanilino) methyl] 4 methylpyridine,

melting at 137-138 [from 3-acetyl-4-methylpyridin and p-chloroaniline];

4-[a-methyl-(4-chloroanilino)methyl]pyridine, melting at 1'07-l08, its dihydrochloride salt melting at 196-198" [from 4-acetylpyridine and p-chloroaniline].

Hon

3-[ot-methyl-(4-ch1oroanilino)methyl]pyridine (73 g.) was dissolved in 333 ml. of ethanol containing 333 ml. of 1 N hydrochloric acid and cooled to 5 in an ice bath. To this cooled solution was added a solution of 24 g. of sodium nitrite in 166 ml. of water over the course of 1 hr. The temperature was kept between 510 during the addition. After the addition was completed, the temperature was allowed to rise to room temperature and the reaction mixture was set aside at room temperature for 18 hours. The oil that separated from the reaction mixture was dissolved in ether and the reaction mixture was thoroughly extracted with ether (4x250 ml.). After drying overnight over anhydrous sodium sulfate the ether solution was concentrated to dryness to yield 58 g. of 3- [a-methyl-(4-chloro-N-nitrosoanilino methyl] pyridine as a thick syrup.

7 By the same procedure as described in detail in this example, the following compounds were prepared:

3 [a methyl-(p-methyl-N-nitrosoanilino)methyl]pyridine from 3-[a-methyl-(p-toluidino)methyl] pyridine;

3 [a-methyl-(pbromoanilino)methyl]pyridine from 3- [on methyl (p bromo-N-nitrosoanilino)methyl]pyridine;

3 [a methyl-(p-rnethoxy-N-nitrosoanilino)methyl]pyridine from 3 [ct-methyl-(p-methoxyanilino)methyl] pyridine;

3 [a-methyl-(3,4-dimethyl-N-nitrosoanilino)methyl] pyridine from 3-[or-methyl-(3,4-dimethylanilino)methyl] pyridine;

2 [a methyl-(4-chloro-N-nitrosoanilino)methyl]pyridene from 2-[oz-methyl-(4-chloroanilino)methyl]pyridine;

2 [a-methyl-(4-chloro-N-nitrosoanilino)methyl] 6- methylpyridine from 2-[a-methyl(4-ch1oroanilino)- methyl]-6-methylpyridine;

[a-methyl-(4-chloro-N-nitrosoanilino)methyl] 2- methylpyridine from [S-a-methyl-(4-chloroanilo)methyl -2-methylpyridine;

3-[a-methyl-(4-chloro-N-nitrosoanilino)methyl] 4-methylpyridine from [3-a-methyl-(4-chloroanilino) methyl]- 4-methylpyridine;

4 [oz methyl-(4-chloro-N-nitrosoanilino)methyl]pyridine from 4-[a-methyl-(4-chloroanilino)methyl]pyridine.

EXAMPLE 3 Preparation of 3- [a-methyl- (4-chloro-N-aminoanilino methyl] pyridine Over the course of 2 hours 133 g. of zinc dust was added portionwise to a stirred solution of 58 g. of 3-[amethyl (4-chloro-N-nitrosoanilino)methyl]pyridine in 250 ml. glacial acetic acid and 75 ml. of water. During the addition of the zinc the temperature of the reaction mixture was held between O5 by means of an ice-salt bath. After the addition, the mixture was stirred for 1 hour at 5 and then for 1 hour at 35. Water (350 ml.) was then added and the reaction mixture was filtered. The filter cake was washed several times with water and the filtrate and the washings 'were combined. Ice (400 g.) was added and the mixture was made strongly alkaline with 6 N sodium hydroxide. The alkaline mixture was extracted with ether (4x250 ml.) and the ether extracts were combined and washed with water (4x100 ml.). When the ether solution had dried overnight over anhydrous sodium sulfate, the desiccant was removed by filtration and the ether was removed by evaporation. 39 g. of 3-[tic-methyl-(4-chloro-N-aminoanilino)methylJpyridine as a thick syrup was obtained.

By the sameprocedure as described in detail in this example, the following compounds were prepared:

3 [0c methyl-(p-methyl-N-nitrosoanilino)methyl]pyridine from 3 [oz-methyl-(p-methyl-N-aminoanilino)- methyl] pyridine;

3 [1-[oi-methyl-(p-bromo-N-aminoanilino)methyl]pyridine from 3-[ix-methyl-(p-bromo-N-nitrosoanilino)- methyl] pyridine;

3 [a methyl-(p-methoxy-N-aminoanilino)methyl]pyridine from 3-[a-methyl-(p-methoxy-N-nitrosoanilino)- methyl] pyridine;

EXAMPLE 4 Preparation of 8-chloro-1,3,4,S-tetrahydro-Z-methyl-S-(amethyl-3-pyridylmethyl -2H-pyrido [4,3- b] indole I mom 1101/ E t O H Fischer Indole A stirred mixture of 14 g. of 3-[a-methyl-(4-chloro-N- aminoanilino)methyl]pyridine, 7.5 g. of l-methylpiperidone-4 and 75 ml. of benzene was heated to reflux. After 24 hours under reflux 0.9 ml. of water was removed from the reaction mixture by means of a Dean-Stark trap and the reaction mixture was concentrated to dryness under reduced pressure. To the stirred residue 56 m1. of 6 N alcoholic hydrogen chloride was added in small portions (5 ml.). After the addition was complete the reaction mixture was refluxed for 0.5 hour, allowed to cool to room temperature and poured onto ice (200 g.). Sodium hydroxide (6 N) was added until the pH was greater than 10 and the alkaline mixture 'was extracted with ether (3x200 ml.). The ether extracts were combined and dried over anhydrous sodium sulfate overnight. The desiccant was removed by filtration and the ether solution was concentrated to dryness to yield 18 grams of solid 8 chloro 1,3,4,5 tetrahydro-Z-methyl-S-(u-methyl-3- pyridylmethyl)-2H-pyrido[4,3-b]indole melting at 107- 108 A small portion was recrystallized from hexane and melted at 108.5110 U.V.

Aigzgropunol The *base (5.0 g.) was dissolved in ethanol and an excess (2.2 moles) of 6 N alcoholic hydrogen chloride was added followed by several volumes of ethyl acetate. The solution was set in the refrigerator at 5 for several hours and the precipitate that separated was collected by filtration. Recrystallized from a mixture of ethyl acetate and ethanol 5.5 g. of 8-chloro-l,3,4,5-tetrahydro-2-meth- By a procedure analogous to that described in detail in this example, and utilizing in place of 3-[a-methyl- (4- chloro-N-arninoanilino)methyl]pyridine, a reactant of the formula --N--N H2 the following compounds were prepared:

Reactant:

Melting or R A Product Boiling Point 4-ehloro... 8-chloro 1,3,4,5tetrahydro-2-methyl- M.P. 110111.

5-(a-methyl-Z-pyridylmethyl) -2H- N pyrido[4,3-b]indole.

The maleate salt M.P. 154156.

Do I 8-ch1oro-1,3,4,5-tetrahydro-2-methyl- B.P. ZIP-216 0.4 mm.

/\ 5-Ia-1nethyl-(6-n1ethyl-2-pyridy1)- N methy1]-2H-pyrido[4,3-b1indole. d-C H3 The dihydroehloride salt M.P. 259261.

Do.. I 8-eh1oro-1,3,4,5-tetrahydro 2 methyl B.P. 217/0.8 mm.

5[a-methyl-(6-methyl-3-pyridyl)- l methyl]-2H-pyrido[4,3-b]indole. K? I CH3 The maleate salt M.P. 184185.

4-brom0... I 8-bromo-1,3,4,5-tetrahydro-2-methyl- B.P. 230-248/0.15 mm. 5-(a-methy1-3-pyridylmethyl)- 2H-pyrido[4,3-b]ind0le.

The maleate salt M.P. l65167.

4-ch1oro-.. I 8-chloro-1,3,4,Metrahydro-Z-methyl- M.P. 191-192.

5- (wrneth yl-4-p yridylmethyl) -2H i pyrido[4,3-b]indole.

The dimaleate hemihydrate salt M.P. 125-126.

4-OH I 1,3,4,5-tetrahydro-2,S-dimethyl-S- B.P. 215225/0.05 mm.

' (amethyl-3-pyridylmethyl)-2H- L pyrido[4,3b]indo1e. I

The maleate salt M.P. 171173.

4-CH O I 1,3,4,5-tetrahydro-8-methoxy-Z- B.P. 225/0.2 mm.

metl1yl-5(a-methyl-3pyridy1- l methyl)-2H-pyrido[4, -b]indole.

The maleate salt M.P. 175176.

3,4-di- I 1,3,4,5-tetrahydro-2,7,8-trimethyl-5- BI. 205210/0.3 mm.

methyl. (a-methyl-3pyridylmethyD-ZH- l py1'ido[4,3-b]indole. N

The maleate salt M.P. 191192.

Do.- I 1,3,4,5-tetrahydr0-2,8,9-trimethyl-5- The maleate salt M.P. 182183.

1 1 EXAMPLE Preparation of 3-(4-ehloroanilinomethyl) pyridine CHO l. NH2

A mixture of 60 g. of p-chloroaniline, 50 g. of 3-pyridy1- aldehyde, 100 mg. of p-toluenesulfonic acid and 300 ml. of benzene was stirred and refluxed for 24 hours. By means of a Dean-Stark trap 7 ml. of water was removed from the refluxing mixture during this time and the reaction mixture was then concentrated to dryness under reduced pressure. To the stirred residue dissolved in 250 ml. of ethanol was added 55 g. of sodium borohydride suspended in 400 ml. of ethanol over the course of two hours. Upon completion of the addition, the reaction mixture was refluxed for 3 hours and then steam distilled for 8 hours to remove any unreacted materials. The solution was then cooled to room temperature and set in the refrigerator for crystallization. The crystalline 3-(4-chloroanilinomethyl)pyridine (85.2 g.) was collected by filtration, M.P. 95-96". A small portion was recrystallized from ethylacetate and hexane and melted at 9899.

The base (5.0 g.) was dissolved in warm ethanol and an excess of 8 N alcoholic hydrogen chloride was added and the mixture was set in the refrigerator to complete the crystallization. The precipitate obtained was filtered and dried yielding 4.5 g. of 3-(4-chloroanilinomethyl) pyridine dihydrochloride, M.P. 170.

By the same procedure as is described in detail in this example, the following compounds were prepared:

2-(4-chloroanilinomethyl)pyridine, melting at 87, its

hydrochloride salt melting at 170 [from p-chloroaniline and Z-pyridylaldehyde];

4-(4-chloroanilinomethyl)pyridine, melting at 93-94,

its dihydrochloride salt melting at l9l-192 [from pchloroaniline and 4-pyridylaldehyde];

4-(p-toluidinomethyl)pyridine, melting at 7374, its dihydrochloride salt melting at l93l94 [from 4- pyridylaldehyde and p-toluidine].

EXAMPLE 6 By the same procedure as is described in detail in Example 2, the following compounds were prepared:

2-(4-chloro-N-nitrosoanilinornethyl)pyridine, from 2-(4- chloroanilinomethyl)pyridine; 4 (4 chloro-N-nitroanilinomethyl) pyridine, from 4-(4- chloro anilinomethyl pyridine; 4-(p-methyl-N-nitrosoanilinomethyl)pyridine, from 4-(ptoluidinomethyl) pyridine.

EXAMPLE 7 By the same procedure as is described in detail in Example 3, the following compounds were prepared:

2-(4-chloro-N aminoanilinomethyl)pyridine from 2-(4- chloro-N-nitrosoanilinomethyl pyridine;

4-(4-chloro-N-aminoanilinomethyl)pyridine from 4-(4- chloro-N-nitrosoanilinomethyl pyridine;

4 (p-methyl-N-aminoanilinomethyl)pyridine from 4-(pmethyl-N-nitrosoanilinomethyl)pyridine.

12 EXAMPLE 8 By the same procedure as is described in detail in Example 4, the following compounds were prepared:

EXAMPLE 9 Pharmaceutical formulations incorporating representative products of this invention were prepared as follows:

Tablet formulation Per tablet, mg. 8 chloro-l,3,4,S-tetrahydro-Z-methyl-S-(ix-methyl- 3 pyridylmethyl)-2H-pyrido- [4,3-b]indo1e dihydrochloride 10.0 Lactose 129.0 Corn starch 50.0 Pregelatinized corn starch 8.0 Calcium stearate 3.0

Total weight 200.0

Procedure (1) 8 chloro-1,3,4,S-tetrahydro-Z-methyl-S-(or-methyl- 3 pyridylmethyl)-2H-pyrido[4,3-b1indole dihydrochloride, lactose, corn starch and pregelatinized corn starch were mixed in a suitable mixer.

(2) The mix was passed through a Fitzpatrick Comminuting Machine fitted with No. 1A screen and with knives forward.

(3) The mixture Was returned to the mixer and moistened with water to a thick paste. The moist mass was passed through a No. 12 screen, and the moist granules were dried on paper lined trays at F.

(4) The dried granules were returned to the mixer, and the calcium stearate was added and mixed well.

(5) The granules were compressed at a tablet weight of 200 mg. using standard concave punches having a diameter of 7 Capsule formulation Per capsule, mg. 8 chloro 1,3,4,S-tetrahydro-Z-methyl-S-(2-pyridylmethyl)-2H-pyrido-[4,3-b]indole maleate 25.5

Lactose 159.5 Corn starch 30.0 Talc 5.0

Total net weight 220.0

Procedure Suppository formulation Per 1.3-gm. suppository, gm. 8-ch1oro l,3,4,5 tetrahydro 2 methyl-S-(amethyl-3-pyridylmethyl)-2H-pyrido [4,3-b]indole dihydrochloride 0.025 Wecobee M (produced by E. F. Drew Co., 522

Fifth Ave., New York 10, NY.) 1.230 Carnauba wax 0.045

Procedure Parenteral formulation, per ampul 8-chloro 1,3,4,5 tetrahydro 2 methyl-S-(Z-pyridylmethy1)-2H-pyrido-[4,3-b]indole maleate-50 mg.

Propylene glycol0.4 cc.

Benzyl alcohol (benzaldehyde free)-0.015 cc.

Ethanol 95 U.S.P.--0.10 cc.

Sodium benzoate48. 8 mg.

Benzoic acid1.2 mg.

Water for injection, q.s.1.0 cc.

Procedure (1) 50 grams of 8-chloro-1,3,4,5-tetrahydro-2-methyl- S-(Z-pyridylmethyl) 2H pyrido[4,3-b]indole maleate were dissolved in 150 cc. of benzyl alcohol; 4,000 cc. of propylene glycol and 1,000 cc. of ethanol were added.

(2) The 12 grams of benzoic acid were dissolved in the above. The 488 grams of sodium benzoate dissolved in 3,000 cc. of water for injection were added. The solution was brought up to final volume of 10,000 cc. with water for injection.

(3) The solution was filtered through an 02 Selas candle, filtered into suitable size ampuls, gassed with N and sealed. It was then autoclaved at 10 p.s.i. for 30 minutes.

We claim:

1. A compound of the formula wherein R is hydrogen, lower alkyl, benzoyl or benzyl; R R R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, hydroxymethyl or trifluoromethyl, provided that at least one of R R R and R is other than hydrogen; R is hydrogen or lower alkyl; and A is wherein R is hydrogen or lower alkyl,

2. A compound in accordance with claim 1, R and R are hydrogen.

3. A compound in accordance with claim 2, R and R are methyl.

4. A compound in accordance with claim 2, R is methyl and R is hydrogen.

5. A compound in accordance with claim 3,

Ais

wherein wherein wherein wherein 6. A compound in accordance with claim 5, wherein R is chloro; [R is hydrogen and R is 6-methyl, i.e., 8- chloro-1,3 ,4,5tetrahydro-2-methyl-5- a-methyl- 6 -methyl Z-pyridyl) methyl] -2H-pyrido [4,3-b] indole.

7. A compound in accordance with claim 5, wherein R is chloro and R and R are hydrogen, i.e., 8-chloro- 1,3,4,5 tetrahydro 2 methyl-5-(a-methyl-2-pyridyl methyl) -2H-pyrido [4, 3 -b] indole.

8. A compound in accordance with claim 4, wherein A is N R7 I 9. A compound in accordance with claim 8, wherein R is chloro and R and R are hydrogen, i.e., 8-chloro- 1,3,4,5 tetrahydro 2-methyl-5-(Z-pyridylmethyl)-2H- pyrido[4,3-b]indole.

10. A compound in accordance with claim 3, wherein A is 11. A compound in accordance with claim 10, wherein R is chloro; R is hydrogen and R is 6-methyl, i.e. 8- chloro l,3,4,5 tetrahydro 2-methyl-5-[w-methyl-(6- methyl-3 -pyridyl) methyl] -2H-pyrido- [4,3 -b] indole.

12. A compound in accordance with claim 10, wherein R is chloro and R and R are hydrogen, i.e., 8-chloro- 1,3,4,5 tetrahydro 2 methyl 5 -(a-methyl-3-pyridylmethyl) -2H-pyrido [4,3 -b] indole.

13. A compound in accordance with claim 10, wherein R is bromo and R and R are hydrogen, i.e., 8-bromo- 1,3,4,5 tetrahydro 2 methyl-5-(a-methyl-3-pyridylmethyl) -2H-pyrido [4,3-b] indole.

14. A compound in accordance with claim 10, wherein R is methyl and R, and R are hydrogen, i.e., 1,3,4,5 tetrahydro 2,8 dimethyl-S-(a-methyl-3-pyridylmethyl)- 2H-pyrido[4,3-b]indole.

15. A compound in accordance with claim 10, wherein R is methoxy and R and R are hydrogen, i.e., 1,3,4,5- tetrahydro 8 methoxy-2-methyl-5-(w-methyl-3-pyridylmethy1)-2H-pyrido[4,3-b1indole.

16. A compound in accordance with claim 10, wherein R and R are methyl and R is hydrogen, i.e., l,3,4,5 tetrahydro-2,7,8-trimethyl-5- (a-methyl-3-pyridylmethyl) 2H-pyrido [4,3 -b] indole.

17. A compound in accordance with claim 4, wherein A is 18. A compound in accordance with claim 17, wherein R is chloro and R and R are hydrogen, i.e., 8-chloro- 15 1,3,4,5 tetrahydro 2-methyl-5-(3-pyridylmethyl)-2H- pyrido[4,3-b]indole.

19. A compound in accordance with claim 3, wherein Ais N 22. A compound in accordance with claim 21, wherein R is chloro and R and R are hydrogen, i.e., 8-chloro- 1,3,4,5 tetrahydro 2-methyl-5-(4-pyridylmethyl)-2H- pyrido [4,3-b]indo1e.

23. A compound in accordance with claim 1, wherein 16 R R R and R are methyl; R and R are hydrogen, and A is R7 LI wherein R is hydrogen, i.e., 1,3,4,5-tetrahydro-2,8,9- trimethyl 5 (a methyl-3-pyridylmethyl)Z-H-pyrido 1O [4,3-b1indole.

References Cited UNITED STATES PATENTS 3/1957 Horlein 260--296 OTHER REFERENCES Kost et al.: Chem. Abstracts, v01. 58, Par. 7917-18 (1963).

HENRY R. JlLES, Primary Examiners A. L. ROTMAN, Assistant Examiner U.S. Cl. X.R. 

